Targeting Prolyl Peptidases in Triple-Negative Breast Cancer
Abstract
Triple negative breast cancer (TNBC) is an aggressive sub-type with limited treatment options and poor prognosis. The most life-threatening aspects of TNBC are therapy resistance and metastasis. To improve survival in TNBC patients it will be necessary block metastasis and decrease tumor cell survival. We identified a protein called PRCP (prolylcarboxypeptidase) that promotes metastasis and survival in breast cancer cells. We found high expression of PRCP in TNBC patients coincides with decreased recurrence-free survival (worse outcome). In a drug screen we identified a potent inhibitor of PRCP and its related family member prolyl endopeptidase (PREP) and showed that it has anti-tumor activity in vivo. The goals of this grant are 1) to determine the molecular mechanism by which PRCP and PREP promotes survival and metastasis and, 2) to test our drug candidate for its ability to reduce TNBC tumor growth and target metastatic TNBC tumors. These goals are pursued in two specific aims. Results obtained so far show that PRCP/PREP inhibition reduces IRS1 and IRS2 protein levels, blocks proliferation, and induces death in multiple TNBC cell lines of different sub-types. These effects appear to result, at least in part, through IRS1/2, AKT, and mTORC1 inhibition. Results also indicate the PRCP/PREP inhibitor we identified can inhibit growth of human TNBC tumors in mice, supporting PRCP/PREP as treatment targets and our inhibitor as a therapeutic agent.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2017
- Accession Number
- AD1036027
Entities
People
- Carl G. Maki
Organizations
- Rush University